Recent progress in cancer cell membrane-based nanoparticles for biomedical applications

1 Introduction

Biomimetic nanotechnology, an emerging interdisciplinary field, involves different disciplines, such as nanomaterials science, mechanical engineering, pharmacology, and clinical medicine. Nanoparticle (NP)-based therapeutics are uniquely able to improve drug loading efficiency, control drug release, and protect drug molecules against undesired degradation [1,2]. NPs are widely used in various medical fields, such as cardiovascular diseases, neurological diseases, malignant neoplasm, orthopedic diseases, and immune system diseases, providing a new approach to various treatment problems [3]. These nanoformulations provide advantages over conventional pharmaceutical formulations in terms of safety and efficiency. However, there are still many inadequacies that limit the application of nanoformulations in biomedicine, including limited tumor penetration and insufficient specificity. Furthermore, nanoformulations are often recognized as foreign materials by the reticuloendothelial system (RES) or the mononuclear phagocytosis system (MPS) [4]. The subsequent rapid clearance from blood circulation by the liver and kidneys results in insufficient drug accumulation in the target tissue [5]. In addition, NPs can interact with proteins to form a protein corona, which affects the intended function of the NPs, resulting in changes of biological behavior and loss of function [6,7]. Moreover, the protein corona can accelerate RES/MPS uptake and interfere with the targeting ability of NPs [8].

The biomimetic technique of cell membrane coating, which employs naturally cell-derived membranes, provides a new approach to address NP deficiencies [9]. The encapsulation of NPs with cell membranes can endow the NPs with biomimetic functions and replicate the biological characteristics derived from the original cells, such as the immune evasion of erythrocytes [10] and platelets [11] and the tumor-targeting ability of stem cells [12], immune cells [13], and cancer cell membranes [14]. In vitro and in vivo studies have demonstrated that cell membrane-coated nanoparticles exhibit higher potency, longer retention, and more significant accumulation than bare nanoparticles in the tumor environment (TME) because of immune evasion and cancer targeting abilities [15]. Moreover, biomimetic nanoparticles provide significant advantages regarding biocompatibility, low cytotoxicity, and structural support [16].

With the rapid development of biomimetic nanotechnology different types of derived membranes have been exploited for the development of novel membrane NP-based therapies, such as erythrocytes [10], platelets [11], cancer cells [14], stem cells [12], immune cells [13], central nervous system-derived cells [17], bacterial outer membrane vesicles [18], and extracellular vesicles [19]. Cancer cell membranes exhibit distinctive advantages because of their easy cultivation and their superior homologous targeting and immune evasion [20]. Cancer cell membrane-based biomimetic nanotechnology provides a new methodology and exhibits promising prospects [21]. Compared to the potential threat of living tumor cells to patients, cell membrane coating nanotechnology is safer during usage because of the inactivation of tumor cells and the removal of intracellular components [22]. In treatments of tumors that lack effective targeting, cancer cells achieve precise delivery of bionanoparticles to different types of tumors through homotypic aggregation to homologous tissues [23]. The encapsulated NPs can specifically accumulate in the tumor tissue and reduce early clearance, thereby prolonging the residence time of the drugs they carry and reducing their systemic side effects [24]. Furthermore, cancer cell membranes also show excellent performance in nontumor diseases such as immune system diseases [25] and cardiovascular diseases [26] because of their rich surface functions that yield immunomodulation [22] and biological barrier penetration [27].

Here, we review recent advances and original research in applying biomimetic NPs coated with tumor cell membranes in the medical field and provide a comprehensive summary of the different diseases and diagnostic and therapeutic methods involved (Figure 1). First, different properties of cancer cell membranes are discussed separately. Cancer cells exhibit unique homotypic targeting to tumor tissues, as well as excellent antiphagocytosis, immunomodulation, and biological barrier penetration abilities. Second, the application of cancer cell-based NPs in different types of diseases are discussed (i.e., malignant neoplasms, hematological malignancies, cardiovascular diseases, and immune system diseases). Third, the integration of cancer cell-based NPs in existing therapeutic and diagnostic strategies is presented and discussed, including radiotherapy, chemotherapy, thermotherapy, reactive oxygen species-related therapies, gene delivery, tumor vaccines, and bioimaging of tumors. Finally, the prospects and challenges for the clinical translation of cancer cell membrane-mimetic NPs are discussed.

[2190-4286-14-24-1]

Figure 1: Application of biomimetic cancer cell membrane-coated nanoparticles in different types of diseases: therapeutic and diagnostic methods. Figure 1 was drawn using Figdraw (https://www.figdraw.com), export ID PSWIPb05cf. The materials contained in the image are copyrighted by Home for Researchers. This content is not subject to CC BY 4.0.

2 The functions of the cancer cell membrane

Different types of proteins present in the cancer cell membrane affect the properties of cancer cells and the way they interact with other cells. The biological effects of nanoformulations can be enhanced through the effective utilization of specific protein groups. A schematic diagram of surface proteins and functions of the cancer cell membrane is shown in Figure 2.

[2190-4286-14-24-2]

Figure 2: Different roles of the cancer cell membrane. Figure 2 was drawn by Figdraw (https://www.figdraw.com), export ID SWOTY96667. The materials contained in the image are copyrighted by Home for Researchers. This content is not subject to CC BY 4.0.

2.1 Homologous targeting

Cancer cells usually exhibit fast growth and easy metastasis [28]. After circulating tumor cells are released from the primary tumor site into the bloodstream, they participate in the main metastasis process and tend to form multicellular homoaggregates at major attachment sites [29,30]. The homotypic aggregation of cancer cells mediates solid tumorigenesis and metastatic behavior [31]. The mechanism of homotypic aggregation is the result of multifactorial action and is closely related to tumor-specific antigens (e.g., Thomsen–Friedenreich antigen [29], carcinoembryonic antigen [32], and glycoprotein 100 [33]) and other adhesion protein ingredients (e.g., EpCAM, N-cadherin, E-cadherin, galectin-1, galectin-3, integrins, CD24, CD44, and CD47 [34-36]) derived from the surface of the cancer cell membrane.

Inspired by these characteristics of cancer cells, biomimetic cancer cell membrane-coated NPs were designed for tumor target delivery. Homotypic cancer cell membrane-modified NPs show stronger targeting capabilities than NPs modified with single ligands [20]. This is attributed to the multiple membrane receptors expressed on cancer cell membranes and their ability to avoid the formation of protein coronas [8,20]. Therefore, cancer cell membrane-encapsulated NPs can achieve better targeting toward tumors.

Fang et al. coated poly (lactic-co-glycolic acid) (PLGA) NPs with the MDA-MB-435 human breast cancer cell membrane. The encapsulated biomimetic NPs exhibited a stronger affinity for cultured MDA-MB-435 cells in vitro than bare NPs and erythrocyte membrane-encapsulated NPs [37]. Homologous targeting was not found in cells derived from normal tissues. Comparing NPs coated with hepatocellular carcinoma (HCC) HepG2 cell membrane and normal hepatocyte L02 cell membrane, only HepG2 cell membrane-coated NPs showed active recognition and targeted delivery to the tumor [31]. The homologous targeting ability of the cancer cell membrane has been further demonstrated in an experimental murine breast metastasis model. Biomimetic NPs can spontaneously selectively accumulate in primary tumors and metastatic nodules after entering the blood circulation [38]. In contrast to the aggregation to homologous tissues, cancer cells have shown low affinity to other tumor tissues. In the SM-SCC-7 tumor model, biomimetic NPs derived from heterotypic tumor cells did not exhibit homologous targeting to tumor tissue (Figure 3A–C). Furthermore, the biomimetic NPs showed active recognition and homing to the same type of tumor but selectively avoided the heterotypic tumor tissue in a dual-type tumor model (Figure 3D–F) [14]. Additionally, it is interesting that sometimes the cancer cell membrane-coated NPs show a certain affinity for other types of cancer cells, which may be attributed to the expression of cross antigens on different cells. Pan et al. found that breast cancer MDA-MB-231 membrane-coated NPs also showed a certain affinity for the cervical cancer cell line HeLa [39].

[2190-4286-14-24-3]

Figure 3: Schematic representation of the distribution of cancer cell membrane-encapsulated NPs in a tumor-bearing mouse model. (A) UM-SCC-7 tumor-bearing mice were injected with Dox (d) and different types of NPs via tail vein (a: UM-SCC-7; b: COS7; c: Hela). (B) Distribution of different NPs with equivalent doses of DOX 24 h after entering UM-SCC-7 tumor-bearing mice. (C) Distribution of iron from NPs in UM-SCC-7 tumor-bearing mice. (D) Biomimetic NPs showed high accumulation only in the same tumor tissue in the dual-type tumor model. (E, F) Fluorescence signal distribution of H22 and UM-SCC-7 membrane-encapsulated NPs. Figure 3 was adapted with permission from [14]. Copyright 2016, American Chemical Society. This content is not subject to CC BY 4.0.

2.2 Modulation of the immune system

Cancer cells exhibit excellent immune surveillance evasion, which allows them to continue to expand and form tumors without being cleared from the organism [40]. The immune evasion of cancer cells is closely related to the proteins present on the cell surface, such as CD47, which is ubiquitously expressed on the membrane of solid tumor cells and sends a “do not eat me” signal to phagocytic cells [41]. CD47 has been shown to avoid uptake by macrophages, which enables the NPs to escape immunogenic clearance [42]. Additionally, CD24 has been found to be overexpressed in several malignant diseases (e.g., ovarian and breast cancer). It also counteracts immune clearance by interacting with Ig-like lectin 10 (Siglec-10) expressed by macrophages [43]. Moreover, PD-L1 and B2M play an important role in preventing macrophage phagocytosis [43]. Most of the protein components can be efficiently retained and transferred to NPs during the encapsulation of cancer cell membranes (Figure 4A) [31]. With these features, although NPs encapsulated by a cancer cell membrane are foreign substances, they can still escape the surveillance of the body, thereby resisting phagocytosis by macrophages and prolonging the blood circulation time [20].

[2190-4286-14-24-4]

Figure 4: Characterization of membrane-encapsulated NPs. (A) Gel electrophoresis analysis showed that liver cancer biomimetic nanoparticles (a) basically retained and transferred the extracted cancer cell membrane protein components (b), which were similar to the cell lysate (c). (B) The box plot shows that the dimensional stability of cancer cell membrane biomimetic nanoparticles in water and PBS is significantly higher than that of bare nanoparticles. Adapted from [31]. (© 2019 Liu X et al., published by Ivyspring International Publisher, distributed under the terms of the Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/).

The intricate membrane protein components of cancer cell membranes play an important role in immune regulation. Researchers have found a number of immune checkpoint signals in cancers that could confer strong immunosuppression on cancer cells by combining ligands with inhibitory immunoreceptors, such as PD-1, TIGIT, CTLA-4, BTLA, LAG3, and TIM3 [44]. Under reasonable utilization, the immunosuppressive property of tumor cells is expected to be applicable to the treatment of autoimmune diseases [22]. Also, numerous types of tumor antigens that are overexpressed on the surface of cancer cell membranes, after being presented to antigen-presenting cells (APCs), will promote the proliferation and infiltration of active T cells in the TME and induce an antigen-specific antitumor response [33,45]. This natural advantage also makes cancer cell membranes useful in nanoimmunotherapy, which can induce specific antitumor immunity through relevant antigens on the surface of biomimetic NPs [46]. Moreover, the tumor antigens associated with biomimetic NPs show promise in inducing long-term immunological memory, which could prevent cancer recurrence [47].

2.3 Other functions

In addition to the above functions, cancer cells have also been found to have the ability to penetrate the blood‒brain barrier (BBB) in some special cases [26,27]. As a highly specialized structure, the BBB maintains homeostasis of the central nervous system [48]. The targeted delivery of drugs to the brain is challenging because of the limited BBB permeability, which restricts the treatment of brain-related diseases [49]. Aggressive metastases to brain tumors are common in various types of tumors, such as melanoma, lung cancer, and breast cancer [27]. These tumor cells are able to cross the BBB and adhere to brain tissue. This process is closely associated with membrane-associated components such as syndecan-1 [50], vascular cell adhesion molecule-1 (VCAM-1), and activated leukocyte cellular adhesion molecule (ALCAM) [51]. In a study on the ability of cancer cell membranes to penetrate the BBB, NPs coated with cell membranes from melanoma B16F10 cells, breast cancer 4T1 cells, and African green monkey kidney fibroblast COS-7 cells were used to compare the penetration in brain tissue. The NPs coated with B16F10 and 4T1 cell membranes showed excellent fluorescence aggregation signals 8 h after the nanoformulations were administered intravenously, while COS-7 cell membrane-coated and bare NPs showed no obvious signal aggregation [52]. Hence, specifically prepared biomimetic NPs may enable the diagnosis and treatment of brain-related diseases. Additionally, the membrane-encapsulated NPs were shown to have better dispersion and longer storage time than bare NPs because of the higher colloidal stability of the prepared colloidal particles [53]. In one study, liver cancer cell membrane-encapsulated PLGA NPs maintained a stable size in water and PBS for a long time, while bare PLGA NPs progressively grew larger (Figure 4B) [31].

3 Application of cancer cell membrane-encapsulated NPs

Regarding current therapies, patients respond differently to the same treatment because of different degrees of disease progression and individual differences and inevitably suffer from a certain degree of toxicity and side effects. Therefore, it is necessary to customize treatments to maximize the benefit of the treatment for the patient at the lowest cost. Cancer cell membranes hold great promise for personalized precision therapy because of their unique homologous targeting properties and immune evasion capabilities. Cancer cell membrane-based biomimetic NPs have been widely used in the diagnosis and treatment of tumor-related diseases (e.g., head and neck tumors [53], gland tumors [9], respiratory system tumors [54], digestive system tumors [55], urinary system tumors [56], gynecological tumors [57], skeletal system tumors [58], and hematological malignancies [59]). Additionally, due to the abundantly expressed functional components, they can play a unique role in specific types of noncancerous diseases, such as cerebrovascular diseases [26] and immune system diseases [22]. Different types of diseases associated with cancer cell membranes are summarized in Table 1 and described in detail in the following sections.

Table 1: Applications of biomimetic cancer cell membrane-coated NPs.

Types of diseases Cell membrane Core nanoparticle Drug In vivo animal model Ref. malignant neoplasms brain tumors B16F10, 4T1 poly(caprolactone) and pluronic copolymer F68 indocyanine green BALB/c nude mice
[52] breast cancer 4T1 lanthanide-doped upconversion NPs doxorubicin female BALB/c nude mice [23] liver cancer HepG2 PLGAa doxorubicin BALB/c nude mice [31] prostate cancer RM-1 mesoporous polydopamine NPs chloroquine male BALB/c nude mice [56] cervical cancer Hela, RBCsb mesoporous prussian blue NPs indomethacin, gamabufotalin female BALB/c mice [57] osteosarcoma 143B, RAW264.7 PLGA paclitaxel male BALB/c nude mice. [58] mematological malignancies leukemia C1498 PLGA CpG oligodeoxynucleotide 1826 C57BL/6 mice [59] multiple myeloma ARD PCECc NPs bortezomib C57BL/KA mice [60] cardiovascular disease ischemic stroke 4T1 pH-sensitive polymeric NPs succinobucol tMCAO ratsd [26] immune system diseases SLEe MHCIf-deficient 4T1 DSPE-PEG2Kg dexamethasone MRL/lpr mice [22]

aPLGA: poly(lactic-co-glycolic acid); bRBCs: red blood cells; cPCEC: poly(ε-caprolactone)-PEG-poly(ε-caprolactone); dtMCAO: transient middle cerebral artery occlusion; eSLE: systemic lupus erythematosus; fMHCI: major histocompatibility complex class I; gDSPE-PEG2K: 1,2-distearoyl-sn-glycero-3-phosphoethanolamine-N-[methoxy(polyethylene glycol)].

3.1 Malignant neoplasms

Insufficient targeting of tumor tissue has hindered patients from further benefiting from therapy. Exploiting the homotypic aggregation behavior during initiation and progression of solid tumors [31], biomimetic cancer cell membrane-coated NPs have shown great promise. This strategy could enable the drug to accumulate in target tissues while reducing accumulation in off-target areas. HCC, a common digestive system tumor, presents the sixth leading cancer incidence and the third leading mortality worldwide [61]. A biomimetic particle model using PLGA NPs as a carrier for the anticancer drug doxorubicin (Dox) encapsulated by the HepG2 liver cancer cell membrane was designed for the treatment of HCC [31]. The HepG2 cell membrane-encapsulated NPs exhibited superior antitumor effects compared to bare NPs and PBS controls under the same treatment conditions in a mouse HCC model. Through homotypic aggregation and immune evasion, as well as the prevention of premature drug leakage from the biomimetic NPs, the drug was efficiently accumulated at the target site. The fluorescence signal showed a predominant accumulation of HepG2 cell membrane-coated NPs in the tumor region after eleven days of intervention, whereas such accumulation was not observed in the bare NP- and PBS-treated groups (Figure 5a). The tumor volume and weight decreased by approximately 90% after eleven days of intervention, while the tumors treated with the bare NPs and PBS showed an increasing growth trend (Figure 5b–d). In addition, all mice showed no significant changes in body weight during the intervention period (Figure 5e) [31]. The efficacy in the HCC model demonstrates the critical role of cancer cell membrane-based NPs in targeting tumors.

[2190-4286-14-24-5]

Figure 5: Antitumor efficacy of cancer cell membrane-coated NPs in a hepatocarcinoma mouse model. Hepatoma HepG2 cell membrane-encapsulated PLGA nanospheres loaded with doxorubicin (Dox-HepM-PLGA) yielded smaller tumor volumes than the bare nanoparticles and the PBS control group. (a) Fluorescence imaging eleven days after intravenous injection of biomimetic nanoformulations. (b) Tumor volume. (c) Tumor weight. (d) Relative tumor volume. (e) Changes in mouse body weight. Adapted from [31]. (© 2019 Liu X et al., published by Ivyspring International Publisher, distributed under the terms of the Creative Commons Attribution 4.0 International License, https://creativecommons.org/licenses/by/4.0/).

Biomimetic cancer cell membrane-encapsulated NPs offer new possibilities regarding cancers that lack therapeutic targets. Breast cancer is the most common malignant tumor in women and the leading cause of cancer death in women [61]. Triple-negative breast cancer (TNBC), as a highly aggressive subtype of breast cancer, accounts for approximately 10–20% of all breast cancers [62]. TNBC shows deficient expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) [62]. The treatment of TNBC mainly relies on chemotherapy and surgical resection. Due to the lack of effective therapeutic targets and its insensitivity and resistance to drugs, TNBC has a high possibility of recurrence and a poor prognosis [63,64]. A type of multifunctional NPs encapsulated with the membrane of 4T1 breast cancer cells was prepared to counteract the insufficient targeting. The 4T1 cell membrane-coated NPs exert multiple antitumor functions after entering the blood circulation and targeting tumor tissues [23]. This targeted strategy, which does not depend on ER, RR, or HER2, shows good prospects for the treatment of metastatic TNBC.

3.2 Hematological malignancies

Malignant tumors originating in the blood and blood-forming systems, such as leukemia, lymphoma, and multiple myeloma (MM), endanger health and life worldwide. Because of the lack of a single location, leukemia cannot be treated with local interventions such as surgical resection. The main therapeutic approaches rely on chemotherapy, and other treatment methods usually cannot to achieve therapeutic effects. Acute myeloid leukemia (AML) is the most common type of leukemia and is characterized by rapid progression and high mortality [65]. Moreover, AML shows a heightened risk of recurrence through minimal residual disease [65,66]. Cancer cell membrane-based NPs have shown unique advantages in the treatment of leukemia. Johnson et al. prepared AML cell membrane-coated NPs with an immunostimulatory adjuvant [59]. The nanoformulation could induce leukemia-associated antigen-specific T-cell responses after the presentation and delivery of leukemia membrane-associated antigens by APCs [59]. These bionanoparticles showed the advantage of multiple antigens and significantly prolonged survival. MM, a malignant proliferation of plasma cells derived from the bone marrow, is the second most common hematological malignancy [67]. Treatment attempts suffer from the inability to effectively target therapeutic drugs into the bone marrow to effectively kill MM cells [60]. MM cell membrane-encapsulated NPs loaded with the first-line treatment drug bortezomib have been designed to address deficiencies in the treatment process [60]. Utilizing membrane-associated proteins for immune evasion and tissues targeting, NPs could effectively target diseased tissues in the bone marrow in mouse models of MM, where they exerted a significant antitumor effect [60].

3.3 Cardiovascular diseases

Ischemic strokes are mainly caused by atherosclerosis and cardiac embolism and can lead to death or disability [68]. Neuroprotection is an important strategy to reduce neurological deficits caused by ischemia/reperfusion injury, but it is difficult to deliver neuroprotective agents to ischemic lesions [69,70]. Inspired by the brain metastasis of some tumors, He et al. tried to apply the 4T1 breast cancer cell membrane to the treatment of ischemic stroke [26]. Expression of syndecan-1 on breast cancer cell membranes promotes migration across the BBB and increases adhesion to perivascular areas of the brain [50]. The transmembrane glycoprotein VCAM-1 (CD106) on the surface of the breast cancer cell membrane mediates adhesion to leukocytes and the early stages of brain metastasis seeding by combining with integrin VLA-1 (α4β1) [51,71]. Utilizing the preferential accumulation of platelets and leukocytes at the site of brain inflammation, the 4T1 breast cancer cell membrane was coated with NPs loaded with succinobucol (SCB), which protected brain cells from ischemia and reperfusion injury. In transient middle cerebral artery occlusion (tMCAO) rat models, the biomimetic NPs showed preferential accumulation in the ischemic hemisphere while efficiently reducing infarct volume and protecting nerves, resulting in significantly higher efficacy than that of the bare NPs (Figure 6) [26]. The ability of cancer cells to penetrate biological barriers has shown promise for targeted drug delivery in cerebrovascular disease.

[2190-4286-14-24-6]

Figure 6: In vivo MRI assay in transient middle cerebral artery occlusion rats. The infarct area of rats treated with 4T1 breast cancer membrane-coated pH-sensitive polymeric nanoparticles loaded with succinobucol (MPP/SCB) was significantly reduced on T2W MRI compared with bare nanoparticles (PP/SCB) and saline (tMCAO). (a) Experimental procedure for rats. (b) MRI visualization of the infarcted regions. Adapted with permission from [26]. Copyright 2021 American Chemical Society. This content is not subject to CC BY 4.0.

3.4 Immune system diseases

Cancer cell membrane-based NPs play a unique therapeutic role in immune system diseases due to their immunomodulatory functions. Systemic lupus erythematosus (SLE) is an incurable chronic autoimmune disease that involves multiorgan damage (e.g., to the skin, joints, kidneys, heart, and brain) [72]. T lymphocytes are considered the key factors in SLE pathogenesis, and the autoantibodies produced by CD4+ T cells will destroy tissues [73]. Utilizing the ability of tumor cell membranes to suppress the immune system, cancer cell membrane-coated NPs enable the regulation of the inflammatory microenvironment. Guo et al. used the major histocompatibility complex class I (MHC I)-deficient 4T1 breast cancer cell membrane to coat dexamethasone (DXM)-loaded biomimetic NPs, endowing them with lower immunogenicity, thus, preventing stimulation of the immune system [22]. The NPs enabled the targeted delivery of DXM to inflammatory regions via the cancer cell membrane-expressed adhesion receptor CD44, which inhibits the expression of inflammation-related components [25]. Furthermore, the highly expressed PD-L1 and CD155 on the cancer cell membrane inhibited the co-receptors PD-1 and TIGHT, thereby targeting disease-related CD4 T cells. The NPs exhibited efficient suppression of the inflammatory environment and promoted homeostasis of the immune system, which shows promise for clinical translation.

4 Combining current therapeutics with cancer cell membrane-encapsulated NPs

With the ongoing exploration of biomimetic nanomedicine for diagnosis and treatment, various modalities based on cancer cell membranes are emerging. Using immune evasion and homotypic targeting of cancer cell membranes, the drug dosage can be effectively reduced by avoiding elimination by the immune system while achieving higher therapeutic benefits and lower normal tissue toxicity. Different types of applications related to cancer cell membranes are summarized in Table 2 and detailed in the following sections.

Table 2: Applications related to biomimetic cancer cell membrane-coated nanotechnology.

Cell membrane types Core nanoparticle Drug Size
(nm) Disease Application

留言 (0)

沒有登入
gif